Inserm U970. Targeting B cell immunity in atherosclerosis. Hafid Ait-Oufella, MD.PhD.
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1 Inserm U97 Targeting B cell immunity in atherosclerosis Hafid Ait-Oufella, MD.PhD.
2 Disclosure : none
3 TNF- IL-1 IL-6 Mac. + IL-6 & TGF IL-1 (h) + Th17 ROR T + IL-8 IL-12 IL-15 IL-18 IL-23 Il-23 IL-21 + IL-17A IL-17F + IL-2 IFN - + Treg SMC Th1 Th Th2 IL-1 TGF TNF- IL-1 IL-6 IL-8 IL-17E + IL-4 IL-5 IL-6 IL-13 + EC VCAM-1 ICAM-1 E-selectin P-selectin IL-1 IL-6 IL-8 IL-18BP Mac. IL-1 IL-33 TGF IL-1ra IL-18BP Anti-inflammatory cytokines Ait-Oufella & Tedgui, ATVB 211
4 T cell Immunity during Atherogenesis 4 Mallat & Tedgui, Expert Opin Biol Ther 24
5 Naive T cell Th IL-12 TGF- Th1 IL-4 TGF- IL-6 Treg T-bet Foxp-3 IFN- Th2 Th17 TGF- IL-1 GATA-3 IL-4, IL-5, IL-13 ROR T IL-21 Pro-atherogenic Th1 Potentially pro-atherogenic Th2 Th17 & atherosclerosis? Anti-atherogenic Treg Ait-Oufella et al. Semin Immun 29
6 B lymphocyte : cellular and humoral functions BCR OXLDL-ab Cytokine production
7 Origin Splanchno-pleural Splanchno-pleural Bone marrow Bone marrow Bone marrow % of splenic B cells 2% <1% 15% >7% Cell surface phenotype CD5 IgM High High High Low IgD Low Low Low High Immune response Innate Rapid T cell-independent Low affinity IgM Adaptative Delayed T cell-dependent Higher affinity IgG
8 B lymphocytes in Human atherosclerotic plaques CD2 staining Houtchkamp et al. J Pathol 21
9 26
10 B cells accumulate in the abdominal Aorta Thoracic Abdominal Very old apoe KO mice High fat diet Grabner et al., J Exp Med 29
11 J Lipid Res 27
12 Deposition of IgM in atherosclerotic lesions Green : IgM Red : CD68 Lewis et al., Circulation 29
13 Natural IgM antibodies are atheroprotective Block the uptake of ox-ldl by macrophages and prevent foam cell formation in vivo (Horkko et al., J Clin Invest 1999) Form complex with minimally Ox-LDL and block their entry into the vascular wall Reduce endothelial cell activation (Chang et al., J Clin Invest 24) Increase uptake of apoptotic cells (Quartiel et al., Eur J Immunol 25)
14 Accelerated atherosclerotic lesion formation in sigm-deficient mice Lewis et al., Circulation 29
15 Binder CJ et al., JCI 24
16 OxLDL immunization induces Th2 response IgM Binder et al. JCI 24
17 IL-5 is required for a protective B cell response in atherosclerosis Binder et al. JCI 24
18 B Cell Pathways in Atherosclerosis Pathogenic oxldl-iggab Others B cell subsets? Teff Mature APC Protective oxldl-igmab oxldl Th2 B1 IL-5 IL-33
19 JCI 22 Ctl Sx Sx+ B * * *
20 Major et al., ATVB 22
21 Puzzling B cells express co-stimulatory molecules B cell depletion is widely used in inflammatory and auto-immune diseases Rheumatoid arthritis Systemic lupus erythematosus. Idiopathic thrombotic thrombocytopenic purpura Autoimmune hemolytic anemia.
22 B cell depletion using anti-cd2 antibody In the blood
23 B cell depletion using anti-cd2 antibody In the spleen
24 Antibodies against oxldl: 6 weeks Ait-Oufella et al., J Exp Med 21
25 Peritoneal B cell subsets <APC-A> <APC-A> IgM <PE-A> B <PE-A> 1 5 B1b B1a <PE-Cy7-A> <PE-Cy7-A> B2=B22+IgM+CD11b-CD5- B1a=B22+IgM+CD11b+CD5+ B1b=B22+IgM+CD11b+CD5- CD11b B <FITC-A> CD <FITC-A>
26
27 T cells within atherosclerotic lesions CTR -CD2 Negative control Ait-Oufella et al., J Exp Med 21
28 T cell activation
29 Cytokine production by CD4+ T cells CTR Anti-CD2 IFN CD4+ %IFN+ among CD4+ cells P=,8
30 DC activation
31 Th17 deviation in B-depleted mice Ait-Oufella et al., J Exp Med 21
32 Il-17 inhibition in vivo abolished atheroprotective effects of B cell depletion CTR -CD2 -CD2 -Il-17
33 B Cell Pathways in Atherosclerosis Pathogenic oxldl-iggab B2 cells T cell co-stimulation and Th1 profile Teff Activation Mature APC Protective oxldl-igmab oxldl Th2 B1 IL-5 IL-33
34 Splenectomy reduces B1a subset in mice Kyaw et al., Circ Res 211
35 Splenectomy induced an increase of atherosclerosis Kyaw et al., Circ Res 211
36 Reconstitution of B1a pool in mice Kyaw et al., Circ Res 211
37 B1a but not B2 transfer reduced atherosclerosis in splenectomized mice Kyaw et al., Circ Res 211
38 B1a but not B2 transfer reduced atherosclerosis in splenectomized miced Kyaw et al., Circ Res 211
39 IgM produced by B1a cells promoted apoptotic cell clearance Kyaw et al., Circ Res 211
40 B Cell Pathways in Atherosclerosis Pathogenic oxldl-iggab B2 cells T cell co-stimulation and Th1 profile Teff Activation Mature APC Protective oxldl-igmab oxldl Th2 B1 IL-5 IL-33
41 B Cell Activation factor (BAFF) Receptor Important for B2 «classical» cells - maturation - survival Expressed by T cells and myeloid cells 3 receptors for BAFF: - BAFFR - TACI - BCMA Implicated in auto-immune diseases SLE Rheumatoid Arthritis Sjogren s Syndrome Anti-Phospholipid syndrome Mackay, Immunol Rev 21 Rauch, PLOS One 29
42 Genetic invalidation of BAFF-r BAFF-R+/+ BAFF-R-/- Pink : T cells Blue : B cells Sasaki et al., J Immunol 24
43 Protocol LDLR KO mice Irradiation (9,5Gy) BM transplantation Wild type BM BAFFr -/- BM 4 WEEKS OF RECOVERY 6-8 WEEKS OF FAT DIET
44 B cell subsets in LDLr/BAFFr mice LDLr/BAFFr+/+ LDLr/BAFFr-/- Sage et al., ATVB 212
45 Activation markers in LDLr/BAFFr mice T cell compartment DC compartment Sage et al., ATVB 212
46 BAFFr invalidation reduced atherosclerosis Plaque size (aortic sinus) Sage et al., ATVB 212
47 Genetic invalidation of BAFFr reduced atherosclerosis Kyaw et al., PLOS One 212
48 Conclusion Immunization BAFF/BAFFr B1a cells -CD2 B2 cells Natural IgM T cells DCs IgG, IgA Apoptotic cell clearance Foam cell formation - Atherosclerosis + Adaptative T cell response and Th1 polarization
49 Thanks Team 5 Alain Tedgui Ziad Mallat Soraya Taleb Stephane Potteaux Melissa Romain Olivier Herbin` Emily Van Vre Padma Ponnuswamy Charlotte Lahoute Lara Khouzami Bruno Esposito Ludivine Laurans Marion Dalloz
50 University of Cambridge British Heart Foundation Andy SAGE Deirdre MURPHY Lauren BAKER James HARRISON Leanne MASTERS Xuan LI Céline LOINARD Fernanda SCHREIBER Nada SALEH CeMM, Medical University of Vienna, Austria Christoph J. BINDER AP-HP, Pierre et Marie Curie University Tabassome SIMON University of Utrecht, The Netherlands Gerard PASTERKAMP Duke University, USA Thomas F. TEDDER
51 Plasma IL-17 & Cardiovascular diseases - Plasma IL-17 at admission - FAST-MI cohort (98 patients enrolled) - Acute ST elevation or non-st elevation Myocardial Infarction - Endpoint : death (all-cause) and recurrent MI at one year After adjustment for cardiovascular risk factors, CRP, and treatments, low IL-17 levels remained an independent correlate of the risk of death or MI Submitted
52 Post-MI Inflammation Inflammatory M onocytes CD11b+ Ly6G+ Apoptosis Ly6C hi 7/4 hi Resident Mo nocytes Ly6C lo 7/4 lo CCR2+ CX3CR1 lo CCR2- CX3CR1 hi Pro-Inflammatory cytokines High Proteolysis Anti-inflammatory cytokines Angiogenesis Ischemic Myocardium Blood
53 % Infarct size LVIDs (mm) LVPWs (mm) % SF B lymphocyte depletion limits adverse LV remodelling LV internal dimension in diastole D14.4 * LV Posterior Wall Thickness in systole D * Shortening Fraction D14 4 * PBS Anti-CD2 PBS Anti-CD2 Infarct Size (Masson Trichrome staining) 5 4 D14 * PBS Anti-CD PBS Anti-CD2 Zouggari*, Ait-Oufella* et al., Submitted
54 IgM deficiency induced accumulation of apoptotic cell within atherosclerotic lesions Fat diet HighFat diet Lewis et al., Circulation 29
55 Role of B lymphocytes in immuno-inflammatory response and tissue remodelling after myocardial infarction
56 Kinetics of inflammatory cell infiltration after Myocardial Infarction Cells/mg tissue Cells/mg tissue LCA ligation Digestion (Col I, XI, Hyaluronidase, DNase) *** Neutrophils (CD11b + Ly6G + 7/4 HI ) *** MI sham Gradient Density Centrifugation FACS Analysis 7/4 HI and 7/4 LOW Monocytes ** *** *** *** ** 7/4 HI MI 7/4 HI MI sham 7/4 LOW MI 7/4 LOW MI sham Days post-mi CD3 + T lymphocytes Days post-mi *** ** * MI sham 5 Days post-mi
57 Kinetics of B lymphocytes infiltration after Myocardial Infarction Flow cytometry analysis B22 Hi IgM + B Cells/mg tissue *** Heart MI sham B22 Immunostaining Days post-mi Sham D5 D5 after MI D14 after MI
![B22 Hi IgM + B Cells/ml Blood [x1 4 ] IgM Anti-CD2 antibody treatment reduces B](/docs-images/90/101419566/images/58-1.jpg "lymphocyte levels B22 Hi IgM + B Cells/spleen [x1 5 ] B22 Hi IgM + B Cells/mg")
58 B22 Hi IgM + B Cells/ml Blood [x1 4 ] IgM Anti-CD2 antibody treatment reduces B lymphocyte levels B22 Hi IgM + B Cells/spleen [x1 5 ] B22 Hi IgM + B Cells/mg tissue B22 Hi IgM + B Cells/mg tissue CD2 mab Mature B cells IgM + 2 g/mouse 1 hour after MI * Blood ** * * PBS Anti-CD Spleen D Anti-CD2 Days post-mi PBS D B CD2 D Heart D3 PBS Anti-CD Heart D5 * PBS Anti-CD2
59 B lymphocyte depletion limits adverse LV remodelling capillaries/myocyte Tunel cells/field Apoptotic cells number (Tunel) PBS Anti-CD2 D * PBS Anti-CD2 Capillary Density (BS1 lectin, WGA) PBS Anti-CD2 D * 1.5 Arteriolar Density ( -actin) PBS Anti-CD2 D14 Arterioles/mm PBS Anti-CD2
60 mrna levels (A.U.) mrna levels (A.U.) B lymphocyte depletion reduces systemic and local post-mi inflammation Spleen D TNF- 1.5 IL1-1.5 IFN- 1.5 IL * *.5 1 * PBS -CD2 PBS -CD2 PBS -CD2 PBS -CD2 Heart D TNF- IL1- IFN- IL ** 1.5 * * PBS -CD2 PBS -CD2 PBS -CD2
61 B lymphocyte depletion alters monocyte distribution in post-mi setting Bone Marrow D3 Blood D3 Monocytes 7/4 HI Cells/ml x1 6 Monocytes 7/4 HI * PBS -CD2 Monocytes 7/4 LOW Cells/ml x1 5 Monocytes 7/4 Lo PBS -CD2 Monocytes 7/4 HI Cells/ml x1 4 Monocytes 7/4 HI * 2 * PBS Anti-CD2 Monocytes 7/4 LOW Cells/ml x Monocytes 7/4 Lo PBS Anti-CD2
62 B lymphocyte depletion selectively reduces MCP-3 levels in post-mi MCP-1/CCL2 1 *** plasma MCP-3/CCL7 plasma MCP-1/CCL2 Not Detected in B cell supernatants D D1 D3 D5 D7 MCP-3/CCL7 45 ** B CD4 and IgMtreated B
63 B lymphocytes trigger 7/4 Hi monocytes migration 7/4 Hi Monocytes transmigration assay Lower compartment : - Medium RPMI 1% SVF - B cells (2.1 6 ) - -CD4 and IgM-treated B lymphocytes 4h Transwell insert (8 m) 7/4 Hi monocytes Microporous col I coated membrane B lymphocytes *** Control B cells Activated B cells *** *** MCP1 MCP3 Control B cells Activated B cells Activated B cells + MCP1 Activated B cells + MCP3
64 Exogenous administration of B lymphocytes promotes adverse LV remodelling Injection splenocytes WT, B cell-depleted splenocytes ± WT or MCP-3-deficient B cells MI FACS Echocardiography Rag1 -/- D-7 D D3 D14 B cells levels 25 2 Spleen D3 # ## *** Spleno WT Spleno CD2 Spleno CD2 +WT B cells Spleno CD2 +MCP3 -/- B cells
65 Exogenous administration of B lymphocytes enhances 7/4 Hi monocytes mobilisation and infiltration into the ischemic heart
66 Exogenous administration of B lymphocytes promotes adverse LV remodelling
B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction
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